AB0401 THE BASELINE SERUM SOLUBLE TNF RECEPTOR LEVELS ARE ASSOCIATED WITH THE RESPONSE OF RHEUMATOID ARTHRITIS PATIENTS TO JAKinibs
Authors: T. Yoshikawa, T. Furukawa, T. Hashimoto, M. Morimoto, N. Azuma, K. Matsui
Journal: Annals of the Rheumatic Diseases (2022)

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the multiple joints. The elucidation of the pathogenesis of RA has progressed dramatically in recent decades, and among the many cytokines involved in the pathogenesis of RA, interleukin (IL)-6 and TNF-α are known to be the major pro-inflammatory cytokines that are abundant in the bloodstream and synovial tissue. JAK inhibitors (JAKinibs) such as tofacitinib and baricitinib are used in the treatment of RA by inhibiting JAK, which in turn inhibits the signaling of various cytokines including IL-6. However, predictors of the response to JAKinibs are still required. Objectives We aimed to combine soluble TNF receptor (sTNFR) I, sTNFR II, IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) levels to identify groups of JAKinibs responses in RA patients. Methods This research is a retrospective study. We reviewed medical records of RA patients initiating JAKinibs between July 2013 and July 2021 in our hospital. The Simplified Disease Activity Index (SDAI) was evaluated at baseline and 3, 6 months after JAKinibs administration. Clinical remission was defined when SDAI decreased ≤ 3.3. Of the 125 patients treated with JAKinibs, 89 patients with 6 months follow-up, valid SDAI and serum available were enrolled. Serum samples were tested for IL-6 (Human IL-6 Quantikine ELISA Kit, R&amp;D systems), sIL-6R (Human soluble IL-6R alpha Quantikine ELISA Kit, R&amp;D systems) and sgp130 (Human soluble gp130 Quantikine ELISA Kit, R&amp;D systems), sTNFR I (Human TNF RI/TNFRSF1A Quantikine ELISA Kit DRT100) and sTNFR II (Human sTNF RII/TNFRSF1B Quantikine ELISA Kit DRT200) using specific ELISAs according to the manufacturer’s instructions. The statistical analyses were performed with EZR 1.55, and p values less than 0.05 were considered significant. Results The median age of patients was 62 (IQR: 51 - 72) years and the median of disease duration was 6.0 (2.0 - 16.0) years. Twenty-seven (30.3%) patients were biologics and Jakinibs naive. The baseline SDAI was median 18.9 (12.7 - 27.9). When comparing SDAI-remission group (clinical remission: CR) and non-remission group, there were no significant differences in any of the baseline clinical parameters. There was no significant difference in the serum levels of IL-6, sIL-6R and sgp130 between the CR and non-CR groups, but the serum levels of sTNFR I and sTNFR II in the CR group were significantly lower than non-CR group. Univariate logistic regression analysis suggested Biologics and JAKinibs naive (odds ratio (OR) 3.58, p = 0.015), baseline Log sTNFR II levels (OR 0.013, P=0.034) as predictors of SDAI remission treated with JAKinibs at 6 months. Although not significant, Stage IV (OR 0.211, P=0.082) and baseline Log sTNFR I serum levels (OR 0.013, P=0.065) were associated with clinical remission. Conclusion RA patients could be easily stratified prior to JAKinibs intervention with serum sTNFR II and sTNFR I levels, not but IL-6 axis cytokines (IL-6, sIL-6R and sgp130). Univariate logistic regression analysis for clinical remission in patients treated with JAKinibs. Odds Ratio [95% C.I.] P Value Age, year 0.973 [0.942 - 1.010] 0.104 Female (%) 0.820 [0.231 - 2.910] 0.759 BMI 0.968 [0.847 - 1.110] 0.627 Duration, year 0.952 [0.897 - 1.010] 0.110 Stage I referrence II 0.857 [0.218 - 3.370] 0.825 III 0.444 [0.072 - 2.740] 0.382 IV 0.211 [0.036 - 1.220] 0.082 Biologic/JAKi naïve 3.580 [1.280 - 9.950] 0.015 JAKi Drug -Baricitinib referrence -Tofacitinib 1.780 [0.659 - 4.800] 0.256 MTX use 1.640 [0.532 - 5.30] 0.390 PSL use 0.476 [0.176 - 1.290] 0.143 SASP use 0.783 [0.268 - 2.290] 0.654 IGU use 0.328 [0.039 - 2.750] 0.304 BUC use 0.436 [0.051 - 3.760] 0.450 TAC use 0.233 [0.029 - 1.910] 0.175 0W IL-6, pg/mL 0.991 [0.977 - 1.000] 0.198 0W sIL-6R, ng/mL 0.983 [0.947 - 1.02] 0.369 0W sgp130, ng/mL 0.998 [0.994 - 1.000] 0.444 0W sTNFR II/I ratio 0.808 [0.222 - 2.940] 0.746 0W Log sTNFR II, pg/mL 0.002 [0.0000653 - 0.634] 0.034 0W Log sTNFR I, pg/mL 0.013 [0.000126 - 1.300] 0.065 Disclosure of Interests None declared